ER-Targeted PET for Initial Staging and Suspected Recurrence in ER-Positive Breast Cancer

Key Points Question Does estrogen receptor (ER)–targeted 16α-18F-fluoro-17β-estradiol (FES) positron emission tomography (PET) computed tomography (CT) perform as well as current standard-of-care imaging (SOC) for staging locally advanced breast cancer or evaluating suspected recurrence? Findings In this diagnostic study of 124 patients with ER-positive breast cancer, there was no statistically significant difference between SOC and experimental FES PET/CT for detection of pathologically proven distant metastases or recurrences. Meaning These findings suggest that FES PET/CT could be considered for staging or detection of recurrence in patients with ER-positive breast cancer.


Introduction
2][3][4][5] As patients with LABC have a high risk for distant metastases at initial diagnosis, they undergo systemic staging with imaging. 6If imaging confirms local disease only, curative-intent therapy with systemic endocrine or chemotherapy, surgery, and radiation therapy is performed. 7If imaging confirms distant metastases, less aggressive palliative systemic therapies are used. 8For patients with suspected recurrence, imaging is used to confirm recurrence, as well as to determine the location and extent of detected disease.These findings impact whether patients will undergo therapy and what therapy modalities are chosen. 6r patients with either LABC or suspected recurrence of BC, National Comprehensive Cancer Network (NCCN) guidelines suggest either computed tomography (CT) of the chest, abdomen, and pelvis with nuclear bone scan or 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) as imaging modalities for systemic staging of disease location and extent. 6There are studies suggesting FDG PET/CT may be superior to CT bone scan 3,9,10 ; however, NCCN guidelines continue to first emphasize CT bone scan, with FDG PET/CT described as "useful in certain circumstances." 6ven NCCN recommendations, many insurances still require CT bone scan to be used for these clinical indications.More recently, imaging targeted by estrogen receptor (ER) status has become clinically available with US Food and Drug Administration (FDA) approval of 16α-18 F-fluoro-17βestradiol (FES) PET. 11,12As 80% of breast malignant neoplasms are ER-positive, FES PET may be valuable in multiple clinical scenarios. 11,12Appropriate Use Criteria for FES PET/CT, developed by the Society of Nuclear Medicine and Molecular Imaging, 13 concluded this imaging modality is useful for evaluation of lesions inconclusive on other tests, for evaluation of lesions that are difficult or dangerous to biopsy, and as a prognostic biomarker when endocrine therapy is considered in patients with ER-positive metastatic breast cancer. 13There are also preliminary studies suggesting FES PET/CT may be superior to FDG PET/CT in patients with invasive lobular carcinoma (ILC) of the breast. 14,15To our knowledge, there are no data comparing FES PET with current standard-of-care imaging (SOC), such as CT bone scan or FDG PET/CT, for staging LABC or evaluating suspected recurrences.This study was designed to determine and compare the detection rate of FES PET/CT vs SOC imaging for distant metastases in patients with ER-positive LABC and recurrences in patients with ER-positive BC and suspected recurrence, using histopathological analysis as the reference standard for confirming a malignant neoplasm.

Methods
This diagnostic study was performed after approval by the WCG institutional review board.All participants provided written informed consent.This study is reported following the Standards for Reporting of Diagnostic Accuracy (STARD) reporting guideline.

Participants
This diagnostic study was conduced as a single-center phase 2 trial (ClinicalTrials.govidentifier: NCT04883814), performed at the Hoag Family Cancer Institute in Irvine, California.Patients were referred to Hoag Molecular Imaging and Therapy by medical and surgical oncologists.Hoag Molecular Imaging and Therapy then screened patients for eligibility, obtained written informed consent, and coordinated trial components.Inclusion criteria were women aged 18 years or older with biopsy-proven ER-positive LABC (cohort 1) or with BC and suspected recurrent disease due to symptom, abnormal tumor marker, or equivocal imaging finding (cohort 2).LABC was defined as anatomic stage IIB to IIIC by the American Joint Committee on Cancer. 16Exclusion criteria were pregnancy or lactation, unwillingness to provide written informed consent, men, and current use of tamoxifen or fulvestrant, which bind estrogen and may prevent accurate FES PET scanning. 17Patients with all histological types of BC were allowed to enroll.Baseline characteristics recorded included age at enrollment, ER immunohistochemistry (IHC; range, 1+ to 3+), progesterone receptor IHC (range, 1+ to 3+), ERBB2 (formerly known as HER2) IHC (range, 0 to 3+), ERBB2 status by ASCO Guidelines 18 (negative or positive), and histology (no special type [previously referred to as invasive ductal carcinoma], ILC, mixed, and mucinous); for cohort 1, we also included the pretrial anatomic stage (IIB, IIIA, IIIB, or IIIC).

Imaging and Interpretation
All enrolled participants underwent SOC imaging (either CT bone scan or FDG PET/CT, as selected by the referring physician) and an experimental FES PET/CT within 14 days of each other with no intervening therapy.For participants receiving CT bone scan, both CT with intravenous contrast of the chest, abdomen, and pelvis, as well as 99m Tc methylene diphosphate nuclear bone scan were performed by standard protocols.For participants receiving FDG PET/CT, patients fasted for at least 4 hours prior to administration of 10 millicurie (mci) (±10%) of FDG, followed by a 60-minute tracer uptake period, then CT and PET imaging from upper thigh proceeding to the skull base on a Siemens Biograph mCT Flow PET/CT system.All participants underwent FES PET/CT, including administration of 9 mci (±10%) of FES, followed by a 60-minute tracer uptake period, then CT and PET imaging on a Siemens Biograph mCT Flow PET/CT system, as described in the Society of Nuclear Medicine and Molecular Imaging Procedure Standard for FES PET. 19Both FDG PET/CT and FES PET/CT were performed without the administration of intravenous contrast.Physicians board certified in diagnostic radiology and nuclear medicine separately interpreted SOC imaging and FES PET/CT (G.A.U.), with blinding to the other modality but not to clinical information.If lesions suspicious for distant metastases (cohort 1) or recurrent malignant neoplasm (cohort 2) were identified on either SOC imaging or FES PET/CT, then 1 suspicious lesion was selected for CT-guided biopsy.Biopsy was performed by a board-certified interventional radiologist (T.P. and T.T.) using imaging to guide biopsy.
Histopathology from biopsy samples was used as the reference standard to confirm presence (true positive) or absence (false positive) of a malignant neoplasm.

Statistical Analysis
The primary end points were the presence of a lesion on FES PET/CT and on SOC imaging histologically proven to represent distant metastasis (cohort 1) or recurrence (cohort 2).For each imaging modality, the true-positive rate was defined as the proportion of patients with biopsyconfirmed disease who had at least 1 lesion detected on imaging.Those detection rates were estimated with exact 95% CIs and were compared between FES PET/CT and SOC imaging using McNemar tests.Positive predictive values were calculated for FES PET/CT and SOC imaging.The cohort sizes of 62 patients in each cohort of the study were selected to allow 80% power to detect a 20% difference in detection rate between SOC imaging and FES PET/CT while controlling the 1-sided type I error rate at 5%.Secondary end points were the sites of distant metastases or recurrences detected by FES PET/CT that were undetected by CT bone scan and incidence of adverse events from FES administration and imaging.Those are reported using descriptive statistics.
Analyses were conducted using R software version 4.2.0 (R Project for Statistical Computing).
Data were analyzed from September 2023 to February 2024.

Results
A total of 177 patients were referred for consideration of eligibility for this study between January 13, 2021, and September 1, 2023.A total of 53 patients were excluded, and 124 patients were included in the analysis (Figure 1).This included 62 participants evaluated in cohort With pathological findings as the reference standard, SOC imaging had 4 false positives in cohort 1 and 2 false positives in cohort 2, such as the example in Figure 2, while FES PET/CT had no false positives in cohort 1 and 1 false positive in cohort 2. When both cohorts were combined, the McNemar P value for a difference between false-positive rates from SOC imaging (6 false positives) and FES PET/CT (1 false positive) was P = .13.When both cohorts were combined, the positive predictive value of FES PET/CT was 96.7% (29 of 30 patients) and the positive predictive value of SOC imaging was 82.4% (28 or 34 patients).
Among 62 patients in cohort 1, 6 (9.7%) had extra-axillary nodes detected on FES PET/CT that were not detected on SOC imaging.As detection of extra-axillary nodes was not a primary aim of the trial, these were not biopsied for pathologic confirmation.There were no participants with extraaxillary nodes detected on SOC imaging but not FES PET/CT.
For the 9 participants in whom distant metastases or recurrences were detected by FES PET/CT but undetected by SOC, the sites of distant metastases were bone (4 patients); bone and nodes (3 patients); bone, pleura, peritoneum, adrenal, and gastrointestinal tract (1 patient) (Figure 2); and chest wall, subcutaneous tissue, and lung (1 patient).For these 9 participants, SOC imaging was CT bone scan in 5 participants and FDG PET/CT in 4 participants.For the 8 participants in whom distant metastases or recurrences were detected by SOC but undetected by FES PET/CT, the sites of metastases were nodes (3 patients), bone (2 patients), bone and liver (1 patient) (Figure 3), bone and adrenal (1 patient), and lung (1 patient).
There were no adverse events reported from FES administration or FES PET CT imaging.There were no adverse events reported from any SOC imaging.

Discussion
This diagnostic study using pathological findings as the reference standard found no significant difference between FES PET/CT and current SOC imaging methods for the detection rate of distant   imaging modality be attempted?Further data will be needed to address this dilemma.
The most common sites of distant metastases and recurrences detected by FES PET/CT not detected by SOC imaging were in bone, followed by lymph nodes.Physiologic excretion of FES in the liver reduces sensitivity of detection of liver metastases by FES.In our study, there were no participants with liver-only metastases or recurrences.
In cohort 1, systemic staging of LABC showed suspicious extra-axillary nodes in 10% of patients with FES PET/CT that were not detected using SOC imaging.While not a primary aim of the trial, the detection of previously unidentified extra-axillary nodal metastases affects staging, prognosis, and treatment. 3,22The ability of FES PET CT to identify extra-axillary nodal metastases requires further evaluation.
We found fewer false-positive findings with FES PET CT (1 false-positive) compared with SOC imaging (6 false positives).Further study of this issue will be needed.
This study was not designed to collect data on management changes.When previously unknown distant metastases are identified in patients with LABC, management and treatment strategies change for most patients. 9Thus, it is highly likely that the identification of distant metastases and sites of recurrence by FES PET will have substantial impact on clinical treatment of patients.
The strengths of this trial include the prospective design and, perhaps most importantly, histologic proof of imaging findings.While imaging is standardly used in patients with cancer, trials with biopsy confirmation are better able to resolve true-positive results from false-positive imaging findings. 23

Limitations
This study has some limitations The weaknesses of this study include the single-center design and the fact that participants in cohort 1 were all stage IIB to IIIB, while the design also called for patients with stage IIIC disease to be included.The patients included in the study had a lower disease rate than assumed during the study design, affecting the power for the primary aims; subgroup analyses were not powered to show differences.Additionally, this diagnostic study was not a randomized trial.Each patient received both SOC imaging and FES PET CT; thus, each patient served as their own internal control for comparison of the different imaging modalities.

JAMA Network Open | Oncology
ER-Targeted PET for Initial Staging and Suspected Recurrence in ER-Positive Breast Cancer

targeted 16α- 18 F
-fluoro-17β-estradiol (FES) positron emission tomography (PET) computed tomography (CT) perform as well as current standard-ofcare imaging (SOC) for staging locally advanced breast cancer or evaluating suspected recurrence?Findings In this diagnostic study of 124 patients with ER-positive breast cancer, there was no statistically significant difference between SOC and experimental FES PET/CT for detection of pathologically proven distant metastases or recurrences.Meaning These findings suggest that FES PET/CT could be considered for staging or detection of recurrence in patients with ER-positive breast cancer.

JAMA
Network Open | Oncology ER-Targeted PET for Initial Staging and Suspected Recurrence in ER-Positive Breast Cancer

Figure 2 .G
Figure 2. Recurrent Disease Detected on 16α-18 F-fluoro-17β-estradiol (FES) Position Emission Tomograph (PET) Computed Tomography (CT) but Not Detected on 18 F-fluorodeoxyglucose (FDG) PET/CT Avid foci A metastases in patients with LABC or recurrences in patients with suspected recurrence.The Institute of Medicine20 and the American Society of Clinical Oncology 21 have emphasized comparative effectiveness research for PET/CT.This study provides comparative effectiveness research for FES PET/CT and suggests FES PET/CT may be considered in patients with ER-positive BC for both systemic staging at initial diagnosis of LABC and evaluation of suspected recurrences.ER-targeted imaging with FES PET/CT is a recently FDA-approved modality, with NCCN guidelines6 and Appropriate Use Criteria13 suggesting several appropriate clinical uses, such as assessing lesions that are difficult to biopsy or evaluation of lesions equivocal on other tests.

JAMA Network Open | Oncology ER
67argeted PET for Initial Staging and Suspected Recurrence in ER-Positive Breast Cancer However, to our knowledge, there were previously no data comparing FES PET/CT with current SOC imaging modalities for staging LABC or evaluating suspected recurrences.This study provides evidence that FES PET/CT performs comparably with current SOC imaging methods for both of these clinical indications.FES detects ER available to bind estrogen ligand, thus FES PET/CT is indicated only for patients with known ER-positive BC.12Patients with ER-negative BC are unlikely to have their disease detected by FES PET, were excluded from this study, and should not be considered for FES PET/CT.17Dayesetal9conducted a prospective trial comparing FDG PET/CT vs CT bone scan for systemic staging of patients with LABC was conducted from 2016 to 2022 and found that FDG PET/CT detected more distant metastases than CT bone scan.A subgroup analysis in our study comparing SOC imaging by FDG PET/CT vs SOC imaging by CT bone scan was limited by the number of events recorded in the subgroups.Our trial began in 2021, before Dayes et al9reported their findings and defined SOC imaging as either CT bone scan or FDG PET/CT, as both are recognized as SOC in NCCN guidelines.6Ofnote, it was common for distant metastases to be detected by only 1 imaging modality.For example, in cohort 2, of 23 patients with pathologically proven recurrent malignant neoplasms, only 11 (47.8%) were identified by both imaging modalities, while 5 (21.7%) were detected only by SOC, and 7 (30.4%)were detected only by FES PET/CT.As more than half of recurrent malignant neoplasms were detected by only 1 imaging modality, the question of how extensive imaging staging should be arises.When there is strong suspicion of recurrence of a malignant neoplasm based on symptoms and laboratory data and one imaging modality finds negative results, should a second JAMA Network Open.2024;7(7):e2423435.doi:10.1001/jamanetworkopen.2024.23435(Reprinted) July 26, 2024 7/10 Downloaded from jamanetwork.comby guest on 08/01/2024